Linking Dentistry and Chronic Inflammatory Autoimmune Diseases - Can Oral and Jawbone Stressors Affect Systemic Symptoms of Atopic Dermatitis? A Case Report.

Background: This case report demonstrates the value of ultrasound measurements, and immunological and toxicological diagnostics in addition to current x-ray imaging procedures to diagnose hidden oral and maxillofacial infections. Using a clear scheme shows the procedure of the authors' steps. The positive impact on the patient's dermatological clinical picture is shown. Functional regeneration using metal-free ceramic implants and autologous bone augmentation is demonstrated. After a healing period, a postoperative control took place. Question: Are chronic inflammatory and chronic toxic stressors from the oral region affecting the patient's state of health and dermatological symptoms? Patients and
Methods: A 52 year old female suffering from neurodermatitis, who had been therapy-resistant for several years, was rehabilitated by oral surgery and prosthetics. Radiological examinations with orthopantomogram (OPG) and three-dimensional imaging (DVT/CBCT) were inconclusive for possible jawbone inflammatory sites. Immunological, toxicological diagnostics and trans-alveolar bone densitometry with ultrasound (TAU), were able to show immunological and toxicological stressors and areas of reduced bone density. Bone densitometry with ultrasound raised the suspicion of silent inflammations in the jawbone with potentially increased cytokine levels.
Results: For the patient incompatible materials, teeth with increased toxin exposure and surrounding softened, fatty, ischaemic bone was removed. Histologies and cytokine profiles were obtained. The resulting defects were functionally regenerated using ceramic implants and autologous augmentation. The cytokine profiles showed significantly elevated RANTES/CCL5, confirming the need for surgical intervention. The patient's atopic dermatitis improved significantly in this case. Summary: Individualized immunological and toxicological diagnostics and trans-alveolar bone density bone densitometry with ultrasound (TAU) identified immunological and toxicological stressors as well as reduced bone density with increased cytokine levels. A therapy-resistant neurodermatitis improved significantly after treatment.
Conclusion: This case report illustrates the need for patient-specific and individualized examinations that link dentistry more closely with other medical conditions in order to clarify possible interactions.

Introduction

With increasing numbers of chronic-systemic, autoimmune diseases and multimorbidities,1–3 health care systems regularly reach their limits.1,4 While the patient’s quality of life is severely affected by these diseases, causes for the rising numbers often remain unclear.5

Interventions in sensitively regulated systems are capable to throw regulations out of balance. Self-healing and compensation of chronic diseases may be suppressed in dysregulated systems. By recovering regulation through eliminating immunological and toxicological stressors, compensation capacity could be strengthened. Surprising successes of the integrative-complementary therapy approach, which cannot be directly explained causally, strengthen this medical approach.6

This is also relevant for neurodermatitis or atopic eczema, a chronic inflammatory skin disease, that can appear in acute and subacute phases. It often affects the scalp, face, and hands and is accompanied by severe itching. Neurodermatitis for that is affecting patient’s quality of life.7,8 This common chronic skin disease is affecting up to 12% of total population.7

Question

This case report highlights possible links between immunological, toxic, and chronic inflammatory stressors in the oral and maxillofacial region and excessive cytokine expressions, chronic diseases and immunological disorders. The associated pathologies are little known, because they often do not clearly show up radiographically. Can further diagnostics and new methods such as trans-alveolar bone densitometry (TAU) with ultrasound clarify these hidden connections? And what other tests (RANTES/cytokines/Titanium/etc.) can be utilized to confirm the type/intensity of the stressor?

Patients and Methods

Case of the Patient

At the beginning of November 2021, a middle-aged female patient presents in our clinic. She has been suffering from eczema on her body, arms, legs and face for years (Figure 1). The woman’s quality of life is significantly reduced.

Figure 1

Dermatological symptoms of the patient’s arm and face.

Dermatologically, neurodermatitis was diagnosed and treated with the following methods: Baths in sodium chloride, systemic and local cortisone treatments, antibiotic therapies, and various forms of nutritional changes. These therapies led to temporary relief of skin reactions and itching but could not permanently eliminate or cure the symptoms. Over time, therapy-resistance resistance set in, and inflammatory phases increasingly intensified.

As a last attempt, the patient presented in our practice clinic with the request to clarify to what extent local oral inflammatory stressors could be contributing to systemic inflammation. Other allergies were not known to date.

Materials and Methods

A comprehensive examination of the oral and maxillary region was performed to identify undiscovered inflammatory stressors that could be contributing to the dermatological symptoms. The patient was informed in advance that examination methods and surgical techniques would be scientifically discussed during the procedure. The patient gave written consent to participate in this case report and to the use of extraoral and intraoral clinical pictures.

The following scheme is intended to illustrate examination steps to diagnose and clarify inflammatory stressors and exclude possible immunologically and toxicologically relevant trigger factors in the maxillo-facial region.

The patient gave its generous agreement to publish the images of her disease and confirmed the written informed consent for us to publish the case details and images. An institutional approval was not required.

Two-Dimensional Radiological Diagnostics (OPG)

The two-dimensional radiographic image (OPG) shows endodontically treated teeth at 25, 34, 45 and 46 after hemisection and titanium implants at 35 and 36. The posterior areas show prosthetic restorations and small radio-opacities in region 48/49 (Figure 2).

Figure 2

Two-dimensional radiographic imaging - OPG (top image) and imaging by trans-alveolar bone densitometry (TAU) with ultrasound: green corresponds to the solid and dense alveolar bone; red corresponds to reduced bone density with suspected osteolytic areas.

Transalveolar Bone Densitometry (TAU) with Ultrasound

After the initial clinical examination excluded acute inflammation, the widely discussed radiographic presentation of chronic inflammatory jawbone pathologies led to further clarification.9 In order to follow the ALARA principle,10 which is part of the Radiation Protection Act, and to clarify possible bone marrow defects or bone marrow edema, ultrasound sonography was performed (Figure 3).11,12

Figure 3

Illustration of a TAU measurement (left image) with ultrasound transmitter extraoral and illuminated ultrasound receiver intraoral. The right image shows the colored imaging of bone density in a single measurement with green for solid and healthy cancellous bone, and red and orange for reduced bone density in the area 38/39 (red circle) as an example.

This preliminary screening shows reduced bone density (red) areas in the wisdom tooth areas, around the endodontically treated teeth and the implants. Reference areas of regular bone density (green) are the bone areas around the healthy, vital teeth (Figure 2).

Three-Dimensional Radiographic Image (DVT/CBCT)

In order to verify the areas of reduced bone density revealed by ultrasound TAU and the resulting suspicion of fatty degenerative osteolysis of the jawbone (FDOJ) with digital bone density measurements according to the validated Hounsfield Units (HU) and to create an implantologic-prosthetic treatment plan,13 a three-dimensional radiographic DVT/CBCT was taken.

The digital bone density measurements taken confirmed the results in the ultrasound TAU. In addition, small radiopaque foreign bodies were detected in the wisdom tooth region 48. Figure 4 shows the measurement of reduced bone density value surrounding a foreign body with the HU value of −273 and therefore a possible malfunction of the local bone metabolism.

Figure 4

Radio-opaque foreign body in region 48 with corresponding osteolytic bone (Hu = −273).

Local Measurement of Volatile Hydrogen Sulfide Toxins on the Endodontic Tooth

Resident anaerobic bacteria such as Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum or Treponema denticola can produce toxic hydrogen sulfide compounds such as methyl mercaptans and thioether compounds in root-canal treated teeth.14

The test* that can be used for this purpose is based on the local detection of the mercaptan/thioether compounds, which diffuse directly into the sulcus of the endodontically treated tooth.15 Paper points are placed into the sulcus and examined for these compounds. This allows the practitioner to evaluate questionable teeth by a non-invasive measuring method. *

Mercaptans/Thioether Sensitisation Test

Studies have shown that protein breakdown products can cause inflammatory reactions and toxic effects, whereby there is no direct correlation to the toxin. The Individual sensitivity is more decisive here. Effector cell typing for mercaptans and thioethers in the laboratory detects an immune reaction to the substances and indicates utilizing the cytokine pattern determined (TH1-IFN-γ/ Treg-IL-10) whether an immune reaction against these substances is taking place at the current time. This sensitivity test thus describes systemic inflammatory reactions and explains the different symptoms associated with the endodontically treated teeth.15,16

Titanium Stimulation Test

The most common cause of individual hypersensitivity to titanium is the excessive proinflammatory reactivity of tissue macrophages. Physiologically, macrophages react after contact with titanium oxide particles by releasing proinflammatory cytokines, specifically TNF-α and interleukin-1. The intensity of cytokine release depends on genetic variants (polymorphisms) of the proinflammatory (IL-1 and TNF-α) and anti-inflammatory (IL-1 receptor antagonist IL- 1RN) mediators involved. The titanium stimulation test was developed and validated for this purpose.17 This whole blood stimulation test reveals whether there is an increased release of TNF-α and/or IL-1β. In patients with positive findings, the macrophages in the titanium implant area react hyperactively to released titanium particles and primarily induce local inflammation.

Determination of RANTES/CCL5 in Serum

RANTES (= Regulated And Normal T cell Expressed and Secreted) is a chemokine with a chemotactic effect. RANTES/CCL5 (R/C) is produced by cytotoxic T lymphocytes (CD28+/ CD8+), neutrophils and eosinophil granulocytes and secreted after activation. Chemotaxis and immune activation are the most essential functions of R/C: R/C is chemotactically active, selectively attracting NK cells, granulocytes, monocytes, and macrophages to an existing area of inflammation. It acts on these cells by binding to surface receptors such as CCR3, CCR5, and CCR1 (CCR = chemokine receptor). R/C is thus involved in many disease patterns in which inflammatory processes occur. Elevated R/C levels are associated with numerous systemic inflammatory diseases. These include rheumatoid diseases, allergies, asthma, multiple sclerosis, and tumor pathologies.16–20

It has been confirmed that increased R/C blood levels are to be evaluated as an indication of a local inflammatory process. This may be caused by FDOJ, as elevated concentrations of R/C have been described here,9,16,17 although R/C as a systemic inflammatory marker, it is not specific for inflammatory jawbone processes. R/C can also increase in the blood in the context of other inflammatory diseases (ie bacterial infections and systemic autoimmune diseases).24 However, if the findings are unremarkable in this respect, R/C does not justify the suspected diagnosis. A normal serum R/C value of 30 ng/mL can be derived from the mean value of scientifically published data.

In the run-up to dental procedures, the patient shows a serum R/C level of 43.4 ng/mL <30 mg/mL.

IMD Laboratory Berlin, Nicolaistraße 22, 12,247 Berlin.

Multiplex Analysis and Quantification RANTES/CCL5 in Samples

The determination of the parameter RANTES/CCL5 in the collected FDOJ samples was performed in the supernatant of the tissue homogenisate on the Luminex ®200™ analyzer and xPonent® software (Luminex, Austin, TX, USA) at the investigating Institute for Medical Diagnostics Nicolaistr. 22, 12,247 Berlin. The procedure has been described in laboratory detail in previous publications.23

Postoperative Histological Findings and Cytokine Profile of the Collected Samples

Histological samples were also taken from the osteolytic parts of the mandibular medulla.

* Institute for Pathology&Cytology; Drs. Zwicknagel/Assmus 85635 Freising, Germany

Results and Rehabilitation

The combination of the described findings results in the medical indication for the surgical intervention of the areas of reduced osseodensification.

The first step is to remove the fatty-degenerated osteolytic tissue (FDOJ) in the first and fourth quadrants, the root canal treated teeth 45 and 46, and the foreign bodies in the wisdom tooth region 48 and retromolar 49.

Subsequently, the FDOJ in the second and third quadrants, the root canal-treated teeth 25, 34, and the metallic implants 35, 36 are removed.

Clinical Diagnosis After the Surgical Opening of the Osteolytic Areas

The areas affected by osteolytic bone marrow defects in ultrasound-TAU sonography (in red) and DVT (HU < −100) were removed with minimally invasive piezosurgery and hand instruments. They are clearly demarcated from the surrounding tissue due to reduced blood flow and fatty degenerative osteolysis of the jawbone (FDOJ). Figures 5 and 6 show clinical examples of such an FDOJ specimens. These are purely medullary processes; the cortical bone is usually intact and demarcated from the cancellous bone, which is softened and interspersed with cavitations.

Figure 5

Characteristic morphology of FDOJ bone sample.

Figure 6

FDOJ bone sample immediately after removal.

Since the pathophysiology of atopic dermatitis via immunological dysregulations25–28 is associated with the inflammatory cytokine RANTES/CCL525–27 in the literature and increased RANTES/CCL5 levels have been found in FDOJ in previous publications,11,22,23 samples of the fatty degeneration are submitted for multiplex analysis of cytokine expression in the laboratory.

Results of the FDOJ Tissue Analyses

Light microscopic examinations of the pathologically conspicuous specimens taken intraoperatively were carried out, with the following findings in two wisdom tooth areas operated on years prior, including retromolar areas in the ascending branch: Assessment area 28/29: “ … In the medullary interiors, a translucent, weakly birefringent coarse foreign material, iron negative, plastic particles are to be considered. The medullary canal shows evidence of a discrete chronic fibrosing osteitis on the one hand and also degenerative changes of the type of interstitial fibrosis and fibrous demarcated fat tissue necrosis. “Assessment area 48/49: “Trophic disorder with myxoid degeneration of the intertrabecular fat marrow with small focal fat necrosis and granular tissue disintegration in some areas; metallic foreign bodies”.

Multiplex Analysis and Quantification of RANTES/CCL5 in the Collected Samples

The multiplex analysis of three FDOJ areas (Figure 7) shows the mean value and comparison to the standard value.19 This corresponds to overexpression of RANTES/CCL5 by approximately 14-fold in the mean of the three FDOJ areas examined. The potential systemic effect of this local overexpression has been discussed in previous studies and case reports.10,19–21,30,31 The graphical comparison of these values is shown in Figure 8.

Figure 7

On average, a concentration of the proinflammatory cytokine RANTES/CCL5 of 2097.5 pg/mL could be detected in the removed tissue in the laboratory multiplex analysis. In healthy cancellous jawbone, 149.9 pg/mL values were measured. Data from Lechner J, von Baehr V. RANTES and fibroblast growth factor 2 in jawbone cavitations: triggers for systemic disease? Int J Gen Med. 2013;6:277–290. doi:10.2147/IJGM.S43852.29

Figure 8

Mean value of RANTES/CCL5 expression from region 28/29, 38/39 and 48/49 compared to a normal value from 19 samples of healthy jawbone cancellous bone.29

Rehabilitation

The fundamental purpose for systemic-immunological dentistry is to eliminate inflammatory triggers and stressors that may set into the jawbone. This is an essential requirement for restoring the long-term functionality of the masticatory organ.

Surgical Rehabilitation

Surgical rehabilitation of a bone marrow defect typical of FDOJ requires a subtle and minimally invasive approach. Frequently, the marrow softening extends to the inferior alveolar nerve. Figure 9 shows the access window into the cortical bone achieved with piezosurgical instruments, and the contents of osteolytic bone.

Figure 9

Example of a surgical sequestration of an extensive FDOJ area.

In order to generate optimal wound and bone healing32–34 as well as functional regeneration of hard and soft tissues, PRF (platelet rich fibrin) is inserted into the resulting cavities after ozone flooding.35,36

Implantological Rehabilitation

After extraction of the endodontically treated teeth 25, 34 and explantation of the titanium implants 35 and 36, the osteolytic bone was carefully removed, then ozone flooding was performed.35,36 In the same session, immediate ceramic implants were placed at sites 25, 34, 35, 36 and delayed implants at sites 45, 46, 47. In region 34–36, a bony augmentation was necessary after osteotomy and extraction of 34 and explantation of 35, 36. This was performed with partial autologous bone from region 38/39 and PRF (Figures 10 and 11). No foreign material was used in order to generate the most biocompatible regeneration possible of healthy new bone.

Figure 10

Third quadrant intraoperatively with the removal of the pathological bone, and placement of ceramic implants 34, 35, 36.

Figure 11

Third quadrant intraoperatively with autologous bone augmentation region 34, 35, 36.

Prosthetic Rehabilitation

After a three-month healing period of the implants and a complication-free wound healing, the patient was restored with metal-free monolithic restoration (Figures 12 and 13). The crowns were conventionally cemented with glass ionomer cement avoiding allergenic plastic adhesives. The crown at site 37 was restored at a later date.

Figure 12

Healed operation site region 35, 36, 37 (osseointegrated ceramic implants surrounded by healthy soft tissue).

Figure 13

Third quadrant prosthetic restoration (monolithic zirconia crowns, cemented).

Management of Ossification of the Chronic Inflammatory Areas

Nine months after complete ossification, a new ultrasound TAU sonography is performed to check the operated FDOJ areas for complete wound healing. The approximately continuous green coloration (lower part in Figure 14) verifies the postoperative inflammation-free bone density. The elimination of inflammatory bone in the jaw could be seen as an immunological necessity for successfully reducing the patient’s dermatological symptoms (Figure 15).

Figure 14

Radiological control image (OPG) with prosthetic restoration (upper image) and control of the metabolic situation of the bone density in the rehabilitated jaw areas with ultrasound TAU sonography (lower image).

Figure 15

Dermatological appearance of the patient’s face before and after completion of treatment.

The Clinical Result of the Initial Dermatological Findings

The patient’s dermatological symptoms increasingly improved after the surgical intervention (Figure 15). Retrospectively, the patient reports a healing success of 85% and a “real game-changer”. The patient has consistently changed her diet and avoids pro-inflammatory foods. Dermatitis and eczema have disappeared mainly except for minor inflammatory-dermatological phases, which can now be resolved with the help of dermatological care. The patient feels a significant improvement in her quality of life due to jaw rehabilitation.

Discussion

Clinical Diagnostics

It is striking that no evidence of chronic inflammation of the jawbone was found in the initial clinical and the two-dimensional radiological diagnostics. The patient was free of pain and complaints in the dental jaw region. Trans-alveolar bone densitometry (TAU) revealed the potentially pathogenic osteolytic areas. The immunological relevance could be confirmed postoperatively in the laboratory via the excessive expression of R/C with the multiplex analyses. Following the legally established ALARA principle8 the positive ultrasound TAU findings (Figure 2) were the medical indication for us to take a 3D image using DVT/CBCT (Figure 4).

Dermatological Pathogenesis Due to Chronic Immunological Dysregulation in the Dental-Jaw Region

Discussion of Local Immune Dysregulation by Titanium Particles

The cytotoxic and DNA-damaging potential of titanium particles has been shown,37,38 in comparison with zirconia particles.39

There were two titanium implants in the mandible on the left in the patient’s initial examination. Studies have demonstrated that titanium particles released into peri-implant tissues are well-known40–44 and terms such as biocorrosion and tribocorrosion (friction+corrosion) are getting more popular in both dentistry and orthopedics.41,45–47

Even from well-healed titanium implants, released particles are capable of provoking39,43 immunological dysregulation and derailments.

The titanium stimulation test conducted by IMD Berlin shows an increased release of inflammatory mediators IL-1b in response to titanium oxide particles. This overreaction of inflammatory mediators is consistent with the reduced bone density in the ultrasound TAU measurement. Figure 2 shows conspicuous red coloration in the ultrasound TAU in the area of the implant at 35 and 36 in the interplant septa. This reduced bone density and associated suspicion of R/C expression was a medical indication to remove the implants and replace them with biologically inert ceramic implants. With the implant removal, surrounding osteolytic tissue was also removed.

Discussion of Local Immune Dysregulation by Endodontically Treated Teeth

The patient’s initial findings included a total of four endodontically treated teeth without radiological abnormalities in the OPG. It becomes increasingly clear that despite implementing the most advanced preparation, disinfection and filling techniques, and utilizing the best materials, a complete absence of bacteria in the root canal system can rarely be achieved.48–52

The literature shows that even from radiographically inconspicuous apical areas of endodontically treated teeth, diffusing toxins such as thioethers and mercaptans are capable of causing immunological dysregulation and derailment.15,16,53,54 The semi-quantitative measurement of biogenic amines diffusing into the sulcus of the endodontically treated tooth listed in Rehabilitation revealed the following toxin values: Tooth 25 = 5, 34 = 2, 45 = 4 and 46 = 4. The threshold value designated as inconspicuous is >2.

In order to deduce the link of local endodontic toxin exposure to systemic immune dysregulation, a mercaptan/thioether sensitization test was performed.16 After in vitro stimulation, this showed a greatly increased Il-10 response (44.7 to <10) to the protein degradation products mercaptans/thioethers. This indicates immunological sensitization by biogenic amines. With the knowledge of the highly stressful systemic disease, this was a medical indication for the removal of the endodontically treated teeth.

As in the peri-implant bone tissue around the two titanium implants, Figure 2 also showed suspicious red areas surrounding the endodontically treated teeth with the ultrasonic TAU. Investigations show that histologically, apical periodontitis is likely to be present in more than half of the root-filled teeth after treatment.55,56

The suspected teeth were therefore replaced with immediate ceramic implants.

Discussion of Local Immune Dysregulation by FDOJ and RANTES/CCL5

Approximately after removing the extensive FDOJ pathologies in the edentulous jawbone areas, around the titanium implants, and in the periapical area of the endodontically treated teeth, the patient’s dermatological symptoms decreased.

These invasive measures were required for reducing the proinflammatory chemokine R/C expression and subsequent systemic-immunological success.

Was this an isolated placebo success or what connections does the scientific literature see between atopic dermatitis and chronic sensitization of the immune system by R/C signaling cascades?

The PubMed search: “atopic dermatitis AND rantes ccl5” from 1994 to 2022 yields a total of 89 results, which we group here according to the activation of RANTES/CCL 5 genes/DNA polymorphism and the direct relation to RANTES/CCL 5 expression:

1. “There was a significant association between the upregulating variant of RANTES −28G and atopic dermatitis, … These results support a role for RANTES promoter polymorphisms in susceptibility to atopic dermatitis”.57

2. “These results suggest that RANTES as well as its receptors CCR3 and CCR5 may play important roles in the orchestration of eosinophil infiltration in ongoing chronic inflammation in atopic eczema, and also reflect the severity of the disease”.58

The PubMed results and the scientists’ statements strengthen the authors’ hypothesis that the reduction of systemic R/C expression by local dental sanitation measures is directly related to clinical outcomes. At the same time, the authors are aware that the complex issues surrounding FDOJ with the inflammatory process chemokines R/C are controversial from various sides.

This case report gives additional space and clinical significance to the demand for large-scale studies for better evidence support.59 The authors agree that there is a need for further studies with significant study designs to provide evidence for this controversially discussed issue. New examination methods, based on technologically advanced ultrasound TAU sonography, are available and increasingly validated.28,29,60

Discussion of Systemic Immune Rehabilitation

Restoring systemic immunological regulation is an essential component of an integrative oral medicine approach. Using autologous blood concentrate (PRF),32–34 ozone flooding35,36 as well as a perioperative optimization of the bone metabolism via the vitamin D3 level,61 a biological-functional regeneration and thus a reduction of the inflammatory load could be achieved.

With the removal and functional regeneration of oral stressors and silent inflammations using autologous and more inert materials, an overreactive immune system could be calmed down and thus regulation brought into homeostasis. Chronic autoimmune diseases such as atopic dermatitis could therefore potentially improve.

The patient’s dermatological symptoms were significantly reduced with the treatment.

Summary

This case report demonstrates a multi-layered protocol for uncovering chronic toxic and chronic immunological exposures in the oral jawbone region. This protocol is complementary to monocausal attributions and highlights the association of oral stresses, immunologic systemic derailments and complex multimorbidities.

There is a possible connection of chronically elevated levels of the proinflammatory chemokine R/C in areas with impaired wound healing, surrounding titanium implants, endodontically pre-treated teeth, and various foreign bodies to systemic disease patterns such as atopic dermatitis.

Even with conventional X-ray diagnostics, areas of reduced bone density in the jaw could be only detected with the addition of TAU measurements. Most notably, the systemic symptoms improved after biological regeneration of the removed FDOJ areas and functional rehabilitation with ceramic implants. Clinical images and data indicate that the hypothetical cause of the patient’s dermatological symptoms was likely a local overexpression of R/C in the surrounding of chronically acting FDOJ areas.

Conclusion

This case can demonstrate for therapists of many specialties the importance of a patient’s dental condition in the development of systemic immunological diseases. It also illustrates the importance and benefit of biocompatible dental treatment in conjunction to appropriate examination procedures.

Although a fundamental therapeutic strategy for atopic dermatitis cannot be derived from this individual case description, the outlook of our work is in line with the new licensing regulations for dentists (ZApprO) in Germany: In dental studies, interdisciplinary thinking should be promoted and problem-oriented to the subject taught.